Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 are associated with gestational duration

Xueping Liu; Dorte Helenius; Line Skotte; Robin N. Beaumont; Matthias Wielscher; Frank Geller; Julius Juodakis; Anubha Mahajan; Jonathan P. Bradfield; Frederick T. J. Lin; Suzanne Vogelezang; Mariona Bustamante; Tarunveer S. Ahluwalia; Niina Pitkänen; Carol A. Wang; Jonas Bačelis; Maria Carolina Borges; Ge Zhang; Bruce A. Bedell; Robert J. Rossi; Kristin Skogstrand; Shouneng Peng; iPSYCH-BROAD Working Group; Wesley Kurt Thompson; Vivek Appadurai; Debbie A. Lawlor; Ilkka E. J. Kalliala; Christine Power; Mark I. McCarthy; Heather Allison Boyd

doi:10.1101/423897

GeneticsbioRxivSep 23, 2018

Preprint

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 are associated with gestational duration

Xueping Liu iD, Dorte Helenius iD, Line Skotte iD, Robin N. Beaumont iD, Matthias Wielscher iD, Frank Geller iD, Julius Juodakis iD, Anubha Mahajan iD, Jonathan P. Bradfield, Frederick T. J. Lin iD, Suzanne Vogelezang, Mariona Bustamante iD, Tarunveer S. Ahluwalia iD, Niina Pitkänen iD, Carol A. Wang iD, Jonas Bačelis iD, Maria Carolina Borges iD, Ge Zhang iD, Bruce A. Bedell, Robert J. Rossi iD, Kristin Skogstrand iD, Shouneng Peng iD, iPSYCH-BROAD Working Group, Wesley Kurt Thompson iD, Vivek Appadurai iD, , Bjarke Feenstra iD

Abstract

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. We conducted a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 was associated with gestational duration; the association was replicated in 9,291 additional infants (combined P = 3.96 x 10-14). Analysis of 15,536 mother-child pairs showed that the association was driven by fetal rather than maternal genotype. Functional experiments showed that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

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